7LL8

D-Protein RFX-V1 Bound to the VEGFR1 Domain 2 Site on VEGF-A

Summary for 7LL8

• Entry DOI: 10.2210/pdb7ll8/pdb
• Descriptor: Isoform L-VEGF189 of Vascular endothelial growth factor A, RFX-V1 (3 entities in total)
• Functional Keywords: d-protein, antagonist, biosynthetic protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 35738.91

Authors

Marinec, P.S.,Landgraf, K.E.,Uppalapati, M.,Chen, G.,Xie, D.,Jiang, Q.,Zhao, Y.,Petriello, A.,Deshayes, K.,Kent, S.B.H.,Ault-Riche, D.,Sidhu, S.S. (deposition date: 2021-02-03, release date: 2021-02-17, Last modification date: 2024-11-06)

Primary citation

Marinec, P.S.,Landgraf, K.E.,Uppalapati, M.,Chen, G.,Xie, D.,Jiang, Q.,Zhao, Y.,Petriello, A.,Deshayes, K.,Kent, S.B.H.,Ault-Riche, D.,Sidhu, S.S.
A Non-immunogenic Bivalent d-Protein Potently Inhibits Retinal Vascularization and Tumor Growth.
Acs Chem.Biol., 16:548-556, 2021

PubMed Abstract: We report a general approach to engineering multivalent d-proteins with antibody-like activities . Mirror-image phage display and structure-guided design were utilized to create a d-protein that uses receptor mimicry to antagonize vascular endothelial growth factor A (VEGF-A). Selections against the d-protein form of VEGF-A using phage-displayed libraries of two different domain scaffolds yielded two proteins that bound distinct receptor interaction sites on VEGF-A. X-ray crystal structures of the d-protein/VEGF-A complexes were used to guide affinity maturation and to construct a heterodimeric d-protein VEGF-A antagonist with picomolar activity. The d-protein VEGF-A antagonist prevented vascular leakage in a rabbit eye model of wet age-related macular degeneration and slowed tumor growth in the MC38 syngeneic mouse tumor model with efficacies comparable to those of approved antibody drugs, and in contrast with antibodies, the d-protein was non-immunogenic during treatment and following subcutaneous immunizations.

PubMed: 33621466
DOI: 10.1021/acschembio.1c00017

Experimental method

X-RAY DIFFRACTION (2.31 Å)